The overall aim of this randomized, sham-controlled clinical trial is to demonstrate that stellate ganglion block (SGB) is an effective and safe non-hormonal intervention for women seeking relief from vasomotor symptoms (VMS) and to identify the physiologic mechanisms underlying this treatment effect. More than 50% of women experience frequent hot flashes and night sweats (i.e., VMS), and these symptoms last on average 7.4 years. VMS are associated with decreased quality of life, increased depressive and anxiety symptoms, sleep disturbance, memory difficulties, and reduced productivity. Safety concerns raised in the Women's Health Initiative (WHI) led to an 80% decline in the use of hormone therapy in the United States. Identifying safe and effective non-hormonal treatments for VMS remains a priority in women's health research. The stellate ganglion, a sympathetic neural structure in the deep tissues of the neck, is commonly blocked with local anesthetics in the treatment of neuropathic and vascular disorders. In open-label intervention studies SGB with local anesthetic reduced VMS by 34 to 90% four weeks to several months after treatment. We conducted the first randomized, sham-controlled (injection of saline into subcutaneous tissue in the neck) trial of SGB (with 0.5% bupivacaine 5 mL) for the treatment of VMS in menopausal women with moderate to very severe VMS (n = 40). A single SGB with local anesthetic significantly reduced moderate-to-very severe VMS by 50% more than sham treatment and lasted for up to sixth months. Analyses of secondary outcomes revealed significant improvements in objectively-measured VMS and trends (p < .10) for improvements in depressive symptoms and memory performance with active SGB compared to sham intervention. In this proposal, we aim to conduct a randomized, sham-controlled clinical trial to more definitively assess the effects of SGB on VMS and to conduct foundational studies to identify the mechanisms of SGB action. The clinical trial will include 220 menopausal women who report 28 or more weekly VMS. Secondary outcomes will include objectively- measured VMS, mood and anxiety, quality of life, sleep, and memory performance. After an initial baseline assessment, women will be reassessed at 3 and 6 months following the SGB or sham intervention. In a subset of 60 women (30 per arm), we will perform a nested, mechanistic substudy built on foundational work in neuroimaging of VMS and ambulatory monitoring of sympathetic nerve activity and telemetry. These two mechanistic outcomes will be obtained at baseline and at 3 months following the intervention. We predict that compared to sham intervention, SGB will reduce the frequency of VMS, improve mood and anxiety, increase quality of life, and improve memory, reduce efferent sympathetic nerve activity and normalize brain activity in thermoregulatory brain areas but have no effect on sleep or other cognitive functions. By providing a more definitive understanding of the effectiveness of SGB, possible secondary benefits, and mechanisms of action, these findings will fill a critical gap in treatment options available to women.